Immunoglobulin-like molecules directed against fibronectin-eda

a technology of immunoglobulin and fibronectin, applied in the field of medicine, can solve the problems of worse cardiac function, increased myocardial infarction-related complications or conditions, and even bigger problems, and achieve the effect of improving angiogenesis and improving angiogenesis

Active Publication Date: 2018-12-06
UMC UTRECHT HLDG BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent describes a method for creating chimeric and humanized antibodies that can help to reduce the risk of rejection or other negative immune responses in humans. These antibodies can also have a longer half-life in the body and can help to prevent, treat, and even reverse the progression of heart disease. The method involves using CDR grafting, chain shuffling, molecular modeling, and other techniques to create highly specific antibodies that can target specific molecules or cells that contribute to the development of heart disease. Overall, this patent shows how these special antibodies can be used to improve cardiac function and potentially save lives.

Problems solved by technology

It becomes an even bigger problem in this era of rapid modernization of developing countries like China and India.
Unfortunately, myocardial infarction-related complications or conditions are increasing because more patients survive the initial life-threatening infarction, but have progressively worse cardiac function afterwards.
Complications after myocardial infarction such as heart failure, fibrosis and arrhythmia result in high mortality rates and morbidity.
Quality of life of those that survive is severely affected as they suffer from progressively decreasing exercise tolerance and reduced capacity to conduct normal daily activities.
The socio-economic burden is nearly €60 billion annually for the USA and EU only, as a consequence of 1) the reduced exercise tolerance and subsequent reduced productivity, 2) expensive medical treatments that are not preventive or curative but decrease symptoms and 3) rehospitalisation.
Despite these advances in blood flow optimization, infarction-related complications still occur and are increasing.
In many patients, the immune system becomes activated in a detrimental way, resulting in inappropriate healing of the heart after myocardial infarction.
Adverse remodelling has several deleterious consequences: heart failure, dilatation and fibrosis of the heart, disturbed contractility and relaxation, and disturbed electrical activation are known complications.
Overexpression of EDA results in enhanced inflammation and injury after brain ischemia.

Method used

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  • Immunoglobulin-like molecules directed against fibronectin-eda
  • Immunoglobulin-like molecules directed against fibronectin-eda
  • Immunoglobulin-like molecules directed against fibronectin-eda

Examples

Experimental program
Comparison scheme
Effect test

example 1

Methods

Peptide Synthesis and Screening Assays

[0221]Linear and CLIPS peptides were synthesized based on the amino acid sequence of the target peptide (i.e. TYSSPEDGIHELFPAPDGEEDTAELQGGC (SEQ ID NO: 27)) using standard Fmoc-chemistry and deprotected using trifluoric acid with scavengers. The linear and CLIPS peptides were short fragments of various length, which may possibly contain the epitope. The constrained CLIPS peptides were synthesized on chemical scaffold in order to reconstruct conformational epitopes, using Chemically Linked Peptides on Scaffolds (CLIPS) technology. For example, the single looped peptides were synthesized containing a dicysteine, which was cyclized by treating with alpha, alpha′-dibromoxylene. The size of the loop was varied by introducing cysteine residues at variable spacing. If other cysteines besides the newly introduced cysteines were present, they were replaced by alanine The side-chains of the multiple cysteines in the peptides were coupled to CLIPS t...

example 2

Animals and Experimental Design

[0226]Male Balb / C wild-type mice (10-12 weeks, 25-30 g) received standard diet and water ad libitum. Myocardial infarction was induced by left coronary artery ligation, just below the left atrial appendage. All animal experiments were performed in accordance with the national guidelines on animal care and with prior approval by the Animal Experimentation Committee of Utrecht University.

Myocardial Infarction In Vivo

[0227]Mice (Balb / C) were anesthetized with a mixture of Fentanyl (Jansen-Cilag) 0.05 mg / kg, Dormicum (Roche) 5 mg / kg and medetomidine 0.5 mg / kg through an intraperitoneal injection. Core body temperature was maintained around 37° C. during surgery by continuous monitoring with a rectal thermometer and automatic heating blanket. Mice were intubated and ventilated (Harvard Apparatus Inc.) with 100% oxygen. The left coronary artery (LCA) was permanently ligated using an 8-0 vicryl suture. Ischemia was confirmed by bleaching of the myocardium and...

example 3

Myocardial Infarction In Vivo

[0231]Male Balb / C wild-type mice (10-12 weeks, 25-30 g) were subjected to the procedure for induction of myocardial infarction as taught herein in example 2. They were also treated with the same antibodies.

Echocardiography

[0232]Mice underwent serial assessments of cardiac dimensions and function by high resolution echocardiography (Vevo 2100, FUJIFILM VisualSonics, Inc., Toronto, Canada) under isoflurane anaesthesia 28 days after myocardial infarction. Long axis and short axis images with 1.0 mm interval between the slices were obtained and used to compute end-diastolic volume (EDV, largest volume) and end-systolic volume (ESV, smallest volume). The ejection fraction (EF) was calculated as 100*(EDV−ESV) / EDV.

Results

Antibodies 27A12.70, 29E7.35, 17G8.72, 42H11.51

[0233]The results showed that relative to mice treated with saline, mice treated with antibodies 27A12.70, 29E7.35, 17G8.72 and 42H11.51 displayed improved heart function following myocardial infar...

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PUM

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Abstract

The present invention is concerned with immunoglobulin (Ig)-like molecules or fragments thereof for use in treatment, prevention, or prevention of progression of adverse cardiac remodelling and conditions resulting from or relating to myocardial infarction and pressure-overload, such as heart failure, aneurysm formation and remote myocardial fibrosis and for use in improving angiogenesis, preferably after ischemic injury. The invention also provides nucleic acid molecules encoding said Ig-like molecules, vectors comprising same, and host cells comprising same.

Description

FIELD OF THE INVENTION[0001]The present invention is in the field of medicine, in particular in the field of cardiology and angiogenesis. The invention provides immunoglobulin (Ig)-like molecules, such as antibodies, and antigen-binding fragments thereof that bind specifically to the EDA-domain of fibronectin-EDA. These Ig-like molecules are particularly suited for treating, preventing or preventing the progression of adverse cardiac or vascular remodelling and myocardial infarction-related complications and for improving or stimulating angiogenesis. The invention also relates to pharmaceutical compositions comprising the Ig-like molecules, e.g., antibodies, or antigen-binding or fragments thereof and methods using the Ig-like molecules, e.g., antibodies, or antigen-binding or fragments thereof for treating, preventing or preventing the progression of myocardial infarction-related complications and adverse cardiac or vascular remodelling and for improving or stimulating angiogenesis...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/18
CPCC07K2317/24C07K2317/20C07K2317/34C07K16/18A61K2039/54A61K2039/505A61K2039/545A61P9/00A61P9/10A61K39/395C07K2317/565
Inventor ARSLAN, FATIH
Owner UMC UTRECHT HLDG BV
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